The chemistry of polyurethanes is extensive and well developed. Typically, polyurethanes are made by a process in which a polyisocyanate is reacted with a molecule having at least two hydrogen atoms reactive with the polyisocyanate, such as a polyol. The resulting polymer can be further reacted with a chain extender, such as a diol or diamine, for example. The polyol or polyamine can be a polyester, polyether, or polycarbonate polyol or polyamine, for example.
Polyurethanes can be tailored to produce a range of products from soft and flexible to hard and rigid. They can be extruded, injection molded, compression molded, and solution spun, for example. Thus, polyurethanes are important biomedical polymers, and are used in implantable devices such as artificial hearts, cardiovascular catheters, pacemaker lead insulation, etc.
Commercially available polyurethanes used for implantable applications include BIOSPAN segmented polyurethanes available from Polymer Technology Group of Berkeley, Calif., PELLETHANE segmented polyurethanes available from Dow Chemical, Midland, Mich., and TECOFLEX segmented polyurethanes available from Thermedics, Inc., Woburn, Mass. These polyurethanes and others are described in the article “Biomedical Uses of Polyurethanes,” by Coury et al., in Advances in Urethane Science and Technology, 9, 130-168, edited by Kurt C. Frisch and Daniel Klempner, Technomic Publishing Co., Lancaster, Pa. (1984). Typically, polyether polyurethanes exhibit more biostability than polyester polyurethanes, and are therefore generally preferred polymers for use in biological applications.
Polyether polyurethane elastomers, such as PELLETHANE 2363-80A (P80A) and 2363-55D (P55D), which are believed to be prepared from polytetramethylene ether glycol (PTMEG) and methylene bis(phenyliisocyanate) (MDI) extended with butanediol (BDO), are widely used for implantable cardiac pacing leads. Pacing leads are insulated wires with electrodes that carry stimuli to tissues and biologic signals back to implanted pulse generators. The use of polyether polyurethane elastomers as insulation on such leads has provided significant advantage over silicone rubber, primarily because of the higher tensile strength and elastic modulus of the polyurethanes.
There is some problem, however, with stress cracking of polyurethanes, particularly polyether polyurethanes. When used in insulation on leads, polyether polyurethanes are susceptible to oxidation in the body, particularly in areas that are under stress. When oxidized, polyether polyurethane elastomers can lose strength and form cracks. This can allow bodily fluids to enter the lead and can compromise the function of the device. It is believed that the ether linkages degrade, perhaps due to metal ion catalyzed oxidative attack at stress points in the material.
One approach to solving this problem has been to coat the conductive wire of the lead. Another approach has been to add an antioxidant to the polyurethane. Antioxidants, however, are sacrificial and eventually can be consumed and leave the polymer unprotected. Yet another approach has been to develop new polyurethanes that are more resistant to oxidative attack. Such polyurethanes include only segments that are resistant to metal induced oxidation, such as hydrocarbon- and carbonate-containing segments. For example, polyurethanes that are substantially free of ether and ester linkages have been developed. This includes the segmented aliphatic polyurethanes of U.S. Pat. No. 4,873,308 (Coury et al.), as well as others disclosed in some of the documents listed below in Table 1. Although such materials produce more stable implantable devices than polyether polyurethanes, there is still a need for polymers, particularly polyurethanes suitable for use as insulation on pacing leads.
The use of polyurethanes in medical devices, however, requires attaining not only desirable stability to oxidation and hydrolysis, and desirable physical properties, but also good processability. Oxidation and/or hydrolysis reactions typically lower molecular weights and diminish the elastomeric properties of polyurethanes. Hydrolytic instability can result from the reaction of water with groups, such as ester, carbonate, amide, imide, and urethane groups that form linkages within the backbone of the elastomer. Some of these groups are more resistant than others, but they all can be hydrolyzed. Oxidative instability results from the reaction of activated singlet oxygen and/or molecular oxygen. Singlet oxygen can react with generally stable chemical moieties such as olefins, and atomic oxygen can react with activated chemical moieties on the elastomer backbone, such as carbon radicals. Polymers that contain groups such as ethers, amides, urethanes, unsaturated carbon groups such as olefins and vinyl groups, and groups containing tertiary carbon atoms are susceptible to oxidation.
Processability is more than the ability to melt process a polymer into some desired geometry. It is the inherent ability of the polymer to develop stable properties after being quenched from the melt. In particular, for segmented polyurethane elastomers, it is the ability of the hard segments of a segmented polymer to crystallize, and preferably phase separate, from the soft segments. The extent and rate at which this happens controls the time it takes to get a part out of a mold, the amount of surface tack a part has, and the geometric stability a part has upon exposure to subsequent processing steps.
Typically, processing additives, such as waxes, are added to reduce surface blocking. Generally, these additives bloom to the surface and cause problems with adhesion. To promote release from an injection mold, surfactants (e.g., soaps) and mold release agents are sprayed onto the mold surface. This helps reduce the adhesion at the interface between the mold and the polymer. The ability of molded parts to retain their geometry while being ejected out of the mold is controlled either by adding additives, which help to promote crystallinity, by increasing cycle time to allow the part to cool and set up before being ejected, or by injecting the elastomer at a lower temperature. This latter technique usually results in greater stress development within the part. The ability of the part to withstand subsequent manufacturing processes is typically controlled by annealing the part. This is done by exposing the part to an elevated temperature (e.g., above the Tg and below the Tm of the polymer) for an extended period of time. It would be desirable to reduce or eliminate processing additives and/or manufacturing steps.
Thus, the identification of materials, particularly polyurethanes, that have the desired stability to oxidation and hydrolysis, and desirable physical properties, as well as good processability, are still needed, particularly for use in implantable medical devices.
TABLE 1aU.S. Pat. Nos.4,234,714Earing et al.4,873,308Coury et al.
TABLE 1bNon-U.S. Patent DocumentsEP 0 624 612 A1Becton Dickinson & Co.
TABLE 1cNonpatent DocumentsBrandwood et al., “Polyurethane Elastomers Containing Novel MacrodiolsII. In Vivo Evaluation”, Fourth World Biomaterials Congress; April 24-28, 1992; Berlin, Federal Republic of Germany; pp. 201.Byrne et al., “Hydroxy Terminated Polyethylene and PolyurethanesPrepared Form it”, Polymer Research Branch, SLCMT-EMP; ArmyMaterials Technology Laboratory; Watertown, MA; pp. 657-658.Byrne et al., “Polyethylene-Based Polyurethane Copolymers and BlockCopolymers”, Army Research Laboratory, Report No. ARL-TR-649;Watertown, MA (November 1994) pp. 1-31.Byrne et al., “Polyethylene-Based Polyurethane Copolymers and BlockCopolymers”, Macromol. Symp., 91, 1-26 (1995).Coury et al., “Biomedical Uses of Polyurethanes”, Advances in UrethaneScience and Technology, 9, 130-168 (1984).Coury et al., “Factors and Interactions Affecting the Performance ofPolyurethane Elastomers in Medical Devices”, Journal of BiomaterialsApplications, 3, pp. 130-179 (Oct. 1988).Fraser et al., “Degradable Cyclooctadiene/Acetal Copolymers: VersatilePrecursors to 1,4-Hydroxytelechelic Polybutadiene and HydroxytelechelicPolyethylene,” Macromolecules, 28, 7256-7261 (1995).Frisch et al., “Polyurethane Elastomers Based Upon Novel Hydrocarbon-Based Diols”, Polymer Institute, University of Detroit Mercy; Detroit,Michigan, pp. 395-416.Hillmyer et al., “The ROMP of COD by a Well-Defined MetathesisCatalyst in the Presence of a Difunctional Chain Transfer Agent:The Preparation of Hydroxy-Telechelic 1,4-Poly(butadiene),” PolymerPreprints, 34, 388-389 (1993).Hillmyer et al., “Chain Transfer in the Ring-Opening MetathesisPolymerization of Cyclooctadiene Using Discrete Metal Alkylidenes,”Macromolecules, 28, 8662-8667 (1995).Hillmyer et al., “Preparation of Hydroxytelechelic Poly(butadiene)via Ring Opening Methathesis Polymerization Employing a Well-DefinedMethathesis Catalyst,” Macromolecules, 25, 872-874 (1993).Hillmyer, “The Preparation of Functionalized Polymers by Ring-OpeningMetathesis Polymerization”, Thesis - California Institute of Technology(1995); Dissertation Services - UMI; Ann Arbor, Michigan; pp. 1-131.Li et al., “Novel Blood-Compatible Polyurethanes ContainingPoly(butadiene) Soft Segments and Phosphatidylcholine Analogues forBiomedical Applications”, Chem., Mater., 8, 1441-1450 (1996).Meijs et al., “Polyurethane Elastomers Containing Novel Macrodiols I.Synthesis and Properties”; Fourth World Biomaterials Congress; April24-28, 1992; Berlin, Federal Republic of Germany; pp. 473.Ward et al., “The Effect of Phase Separation and End Group Chemistryon In Vivo Biostability of Polyurethanes”, ASAIO (1996), Washington,D.C.Ward et al., “Thermoplastic Siloxane-Urethane Block Copolymers andTerpolymers for Biochemical Use”; Third World Biomaterials Congress;April 21-25, 1988; Kyoto, Japan; pp. 433.Yokelson et al., “New Hydrocarbon-based Diols for PolyurethaneElastomers”, Polyurethanes 95: Proceedings of the Polyurethanes1995 Conference Sponsored by the SPI Polyurethanes Division; September26-29, 1995; Chicago, Illinois; pp. 100-108.